Project Summary In 2015, an estimated 7.75 million Americans experienced symptoms of osteoarthritis (OA) that could be associated with a known joint injury. Due to a lack of disease modifying therapies, joint replacement surgery is often the only treatment option to eliminate the associated discomfort and restore mobility for patients with post traumatic osteoarthritis (PTOA). Anti-inflammatory therapy has been proposed to inhibit key factors that have a well-known role in mediating joint inflammation and subsequent tissue damage in PTOA. However, due to significant risks that are associated with exposing the patient to anti-inflammatory drugs outside of the target tissue, it is preferable to inject them directly into the affected joint. Unfortunately, currently available drugs for this purpose are rapidly cleared from the joint space, and they need to be re-administered at least weekly to maintain a therapeutic effect. Thus, this potentially disease modifying treatment strategy for PTOA is limited b y the high frequency of drug dosing that would be required. To enable longer-acting drug activity within a specific tissue, we have developed a platform biotechnology for generating clusters of anti-inflammatory drugs to improve their clinical performance. We can control the number of drug repeats in each cluster to engineer their potency and duration of bioactivity. In our preliminary studies, drugs that have been modified using our technology exhibited superior treatment effects to inhibit inflammation compared to equivalent doses of an unmodified version of each drug. We believe a new drug based on our technology will remain within the joint for at least 12 weeks after administration. Therefore, our strategy is well suited to provide long-term inhibition of inflammation in a joint after injury and prevent further inflammation-mediated joint damage. In this project, we will show how increasing the size of our drug clusters will generate sustained treatment effects in the joint space to inhibit injury-induced inflammation and prevent further damage from accumulating in the joint. As a part of this project, we will measure the amount of time that our drug remains in the joint compared to currently available products. We will also verify that a longer residence time in the joint will be sufficient to prevent the development of PTOA using a preclinical model. This project will demonstrate proof-of-concept for our technology to provide sustained anti-inflammatory therapy in a joint after injury.